Depression is a common mental disorder affecting people across the lifespan, with first onset frequently occurring in the teenage years. The disorder is costly to society and constitutes one of the leading causes of disability in youths and adults worldwide. Research demonstrates that depression in childhood or adolescence is linked to adverse adult consequences, including mental health problems, physical health issues, various social difficulties, and economic hardships. While the specific factors and mechanisms associated with these long-term adversities are not well understood, previous studies point to the relevance of considering the heterogeneity in early-life depression.

The overarching aim of this doctoral thesis was to shed more light on long-term outcomes of childhood and adolescent depression across multiple life domains. This work made use of extensive follow-up data gathered in Sweden and USA, as part of two community-based longitudinal cohort studies of depressed and nondepressed youths prospectively followed into adulthood. In the Uppsala Longitudinal Adolescent Depression Study, participants were interviewed around age 16 (n=631) and age 31 (n=409). Using linkage to nationwide population-based registries, participants were followed up around age 40 (n=576). In the Great Smoky Mountains Study, participants were interviewed at repeated occasions in childhood and adolescence (n=1,420), and at further follow-ups in adulthood extending up to age 30 (n=1,336).

Findings from this work suggest that childhood/adolescent depression can have long-lasting associations with a broad spectrum of adverse outcomes. First, the risk of adult depression is known to be elevated among those exposed to depression in early life; however, depressed youths experiencing major conflicts with parents may be at an additionally increased risk of subsequent depression recurrence. Second, early-life depression was found to be associated with higher levels of adult psychiatric disorders, and also with worse health, criminal, and social functioning, even when accounting for a multitude of potential confounders. Third, early-life depression was predictive of poor labor market outcomes, especially for those with persistent depression. This link was partially mediated by the course of depression. Fourth, the welfare burden associated with early depression amounted to considerable public expenditures in adulthood, particularly for those with persistent depression or comorbid psychiatric conditions such as anxiety and disruptive behavior disorders.

The adverse long-term consequences in the wake of early-life depression underscore the importance of prevention and treatment approaches that are both efficacious and cost-effective. Such targeted efforts may have the potential to avert later ill-health, impairment, and possibly also economic disadvantage.

Experiencing conflictual relations with one's parents while growing up has been linked to onset, recurrence, and worse treatment outcome of adolescent depression. While this suggests that significant problems in the parent-youth relationship make depressive disorders more relentless, it is not clear whether this effect lasts into adulthood. Our aim was to examine if major and minor conflict with parents while growing up predicts depression in adulthood in youth with and without a history of depression. We utilized data from the Uppsala Longitudinal Adolescent Depression Study. This community-based cohort was assessed with structured diagnostic interviews both at age 16-17 and at follow-up 15 years later. The analyses included 382 individuals (227 with a history of child or adolescent depression; 155 peers without such a history). Binary logistic regression was used, adjusting for sex, disruptive behavior disorders, and additional family-related adversities. Among individuals with adolescent depression, major conflict with parents was strongly associated with adult depression (adjusted OR 2.28, 95% CI 1.07-4.87). While major conflict with parents was rare among non-depressed controls, a non-significant association of similar magnitude was still observed. Minor conflict, on the other hand, was not significantly associated with adult depression. Overall, conflict with parents did not predict adult anxiety disorders, substance use, suicidal behavior, somatoform disorders, or psychotic disorders. In conclusion, major parent-youth conflict during upbringing seems to be linked with an increased risk of depression in adulthood. These findings underscore the need to consider contextual/familial factors in the prevention and clinical management of early-life depression.

Adolescent depression is linked to adult ill-health and functional impairment, but recent research suggests that individual/contextual factors might account for this association. This study aimed to test whether the clinical heterogeneity of adolescent depression is related to marginalization from the labor market across early to middle adulthood. Data were drawn from the Uppsala Longitudinal Adolescent Depression Study, a community-based cohort initially assessed with structured clinical interviews at age 16-17. The cohort (n = 321 depressed; n = 218 nondepressed) was followed up after 2+ decades through linkage to nationwide population-based registries. Outcomes included consecutive annual data on unemployment, work disability, social welfare recipiency, and a composite marginalization measure, spanning from age 21 to 40. Longitudinal associations were examined using logistic regression analysis in a generalized estimating equations modeling framework. Subsequent depressive episodes and educational attainment in early adulthood were explored as potential pathways. The results showed that adolescent depression was associated with adult marginalization outcomes, but the strength of association varied across depressed subgroups. Adolescents with persistent depressive disorder had higher odds of all outcomes, including the composite marginalization measure (adjusted OR = 2.0, 95% CI = 1.4-2.7, p < 0.001), and this was partially (31%) mediated by subsequent depressive episodes in early adulthood. Exploratory moderation analysis revealed that entry into tertiary education mitigated the association with later marginalization, but only for adolescents with episodic major depression. In conclusion, the risk for future labor market marginalization is elevated among depressed adolescents, particularly those presenting with persistent depressive disorder. Targeted interventions seem crucial to mitigate the long-lasting impact of early-onset depression.

Purpose: To present the Uppsala Longitudinal Adolescent Depression Study, initiated in Uppsala, Sweden, in the early 1990s. The initial aim of this epidemiological investigation was to study the prevalence, characteristics and correlates of adolescent depression, and has subsequently expanded to include a broad range of social, economic and health-related long-term outcomes and cost-of-illness analyses.

Participants: The source population was first-year students (aged 16-17) in upper-secondary schools in Uppsala during 1991-1992, of which 2300 (93%) were screened for depression. Adolescents with positive screening and sex/age-matched peers were invited to a comprehensive assessment. A total of 631 adolescents (78% females) completed this assessment, and 409 subsequently completed a 15year follow-up assessment. At both occasions, extensive information was collected on mental disorders, personality and psychosocial situation. Detailed social, economic and health-related data from 1993 onwards have recently been obtained from the Swedish national registries for 576 of the original participants and an age-matched reference population (N=200 000).

Findings to date: The adolescent lifetime prevalence of a major depressive episode was estimated to be 11.4%. Recurrence in young adulthood was reported by the majority, with a particularly poor prognosis for those with a persistent depressive disorder or multiple somatic symptoms. Adolescent depression was also associated with an increased risk of other adversities in adulthood, including additional mental health conditions, low educational attainment and problems related to intimate relationships.

Future plans: Longitudinal studies of adolescent depression are rare and must be responsibly managed and utilised. We therefore intend to follow the cohort continuously by means of registries. Currently, the participants are approaching mid-adulthood. At this stage, we are focusing on the overall long-term burden of adolescent depression. For this purpose, the research group has incorporated expertise in health economics. We would also welcome extended collaboration with researchers managing similar datasets.

PURPOSE: Depression at all ages is recognized as a global public health concern, but less is known about the welfare burden following early-life depression. This study aimed to (1) estimate the magnitude of associations between depression in adolescence and social transfer payments in adulthood; and (2) address the impact of major comorbid psychopathology on these associations.

METHODS: This is a longitudinal cohort study of 539 participants assessed at age 16-17 using structured diagnostic interviews. An ongoing 25-year follow-up linked the cohort (n = 321 depressed; n = 218 nondepressed) to nationwide population-based registries. Outcomes included consecutive annual data on social transfer payments due to unemployment, work disability, and public assistance, spanning from age 18 to 40. Parameter estimations used the generalized estimating equations approach.

RESULTS: Adolescent depression was associated with all forms of social transfer payments. The estimated overall payment per person and year was 938 USD (95% CI 551-1326) over and above the amount received by nondepressed controls. Persistent depressive disorder was associated with higher recipiency across all outcomes, whereas the pattern of findings was less clear for subthreshold and episodic major depression. Moreover, depressed adolescents presenting with comorbid anxiety and disruptive behavior disorders evidenced particularly high recipiency, exceeding the nondepressed controls with an estimated 1753 USD (95% CI 887-2620).

CONCLUSION: Adolescent depression is associated with considerable public expenditures across early-to-middle adulthood, especially for those exposed to chronic/persistent depression and psychiatric comorbidities. This finding suggests that the clinical heterogeneity of early-life depression needs to be considered from a longer-term societal perspective.

IMPORTANCE Mental health problems in early life are associated with labor market marginalization, especially in youths with persistent internalizing and externalizing problems. However, previous research has not adjusted for familial (genetic and shared environmental) factors.

OBJECTIVE To examine associations of early-life internalizing and externalizing problems with adulthood unemployment and work disability, adjusting for familial factors.

DESIGN, SETTING, AND PARTICIPANTS This population-based prospective cohort study included Swedish twins whowere born in 1985-1986 and surveyed at 4 consecutivewaves across childhood and adolescence until 2005. Through linkage to nationwide registries, participants were followed up from 2006 to 2018. Data analyses were conducted between September 2022 and April 2023.

EXPOSURES Internalizing and externalizing problems, assessed with the Child Behavior Checklist. Participants were differentiated regarding duration of internalizing and externalizing problems (persistent, episodic, and noncases).

MAIN OUTCOMES AND MEASURES Unemployment (180 days or more of being unemployed) and work disability (60 days or more of being sickness absent or disability pensioned) during follow-up. Cox proportional hazards regression models were calculated to obtain cause-specific hazard ratios (HRs) with 95% CIs in the whole cohort and exposure-discordant twin pairs.

RESULTS Of 2845 participants, 1464 (51.5%) were female. Incident unemployment was experienced by 944 (33.2%) and incidentwork disability by 522 (18.3%) participants. Compared with noncases, persistent internalizing problemswere associated with unemployment (HR, 1.56; 95% CI, 1.27-1.92) and work disability (HR, 2.32; 95% CI, 1.80-2.99). Similarly, compared with noncases, persistent externalizing problems were associated with unemployment (HR, 1.87; 95% CI, 1.55-2.26) andwork disability (HR, 2.38; 95% CI, 1.87-3.03). Persistent cases had overall higher risks of adverse outcomes than episodic cases. After adjustment for familial factors, associations with unemployment were no longer statistically significant, whereas associations with work disability remained or were only slightly reduced.

CONCLUSIONS AND RELEVANCE In this cohort study of young Swedish twins, familial factors explained the associations between early-life persistent internalizing and externalizing problems and unemployment; such factors were comparatively less important for the association with work disability. This suggests nonshared environmental factors may be important for the risk of future work disability among young individuals with persistent internalizing and externalizing problems.

Background: Depression and anxiety are associated with increased risk of sickness absence (SA), yet the developmental patterns of SA remain unclear. We aimed to identify trajectories of SA in young adults with depression and/or anxiety, accounting for sociodemographic and occupational factors.

Methods: Longitudinal study of 1445 twin individuals with elevated depressive/anxiety symptoms in late adolescence or young adulthood (age range: 19-30), assessed in Swedish surveys completed in 2005. Through linkage to nationwide registries, individuals were prospectively followed from 2006 to 2018. The outcome included consecutive annual days of SA, which were analyzed using group-based trajectory modeling. Multinomial logistic regression estimating odds ratios (OR) with 95 % confidence intervals (CI) was used to examine associations of age, sex, and educational level with the resulting SA trajectories.

Results: Four distinct SA trajectories were identified in the total sample: 'high-increasing' (6 %), 'low-increasing' (12 %), 'high-decreasing' (13 %), and 'low-constant' (69 %). Increasing age was associated with higher odds of belonging to the low-increasing trajectory (OR = 1.07, 95 % CI = 1.02-1.12). Women had higher odds of belonging to the low-increasing trajectory (OR = 1.67, 95 % CI = 1.10-2.53), compared with men. Higher education was associated with lower odds of belonging to high-increasing (OR = 0.34, 95 % CI = 0.22-0.54) and high-decreasing (OR = 0.59, 95 % CI = 0.43-0.81) trajectories, compared with lower education. Few differences were observed in analyses stratified by occupational sector.

Limitations: Information on potential confounders (e.g., psychiatric comorbidity, work-environment factors) was not available.

Conclusions: Among young adults with prior depression/anxiety, close to every fifth showed rising SA trajectories over time. This calls for targeted strategies to improve public mental health already at young ages.

Objective: This study aimed to describe the quantity, scope, and fundamental characteristics of recently published randomized controlled trials (RCTs) of psychological interventions.

Methods: We queried two major databases (PsycINFO and PubMeD) for primary reports published in 2010 of RCTs of psychological interventions for participants with a medical condition. We collected data on the characteristics of the trials, participants, interventions, outcomes, and reports.

Results: Of 3,696 retrieved reports 295 primary publications were included. About half (53%) of trials included participants with a mental disorder and more than half evaluated interventions based on a cognitive behavioral therapy (CBT) framework. A majority of trials recruited participants in North America and Europe (79%). A minority of the trials focused on children and adolescents (17%) or the elderly (8%). The median sample size of the intervention arm was n = 41. Thirty-nine percent of trials reported solely patient-reported outcomes. Only 5% of reports indicated funding from for-profit organizations. The median 2010 impact factor of the journals in which reports were published was 2.96.

Conclusion: This snapshot of the research on psychological interventions suggests that the evidence base for psychological interventions is expanding mainly for CBT interventions for adults in high-income countries. Although the restrictive inclusion criteria limit the generalizability of these results, researchers and funding agencies might be advised to strive for greater diversity regarding interventions, geographical/cultural settings and age groups. Regularly updated reviews of this research field, with gradually refined methodology and increased scope, may further inform funders and researchers.

Depression and alcohol use disorder (AUD) are frequently co-occurring in adolescence, which often goes undetected in routine care. While this may potentially compromise treatment effectiveness and lead to a less favourable long-term prognosis, few longitudinal studies have followed this group into adulthood. The aim of this study was to explore the risk for adult depression, anxiety disorders, suicidality, and AUD in adolescents with concurrent depression and AUD. The study was based on the Uppsala Longitudinal Adolescent Depression Study (ULADS), a Swedish prospective cohort study. Diagnostic interviews were conducted in adolescence (age 16-17) and adulthood (around age 30). Adolescents with concurrent depression and AUD (n = 38) were compared with peers having only depression (n = 189) or neither of the conditions (n = 144). Logistic regression was used to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Adolescents with concurrent depression and AUD were more likely than their non-affected peers to experience adult depressive episodes (aOR, 5.33; 95% CI, 2.22-12.83), anxiety disorders (4.05; 1.77-9.27), suicidality (5.37; 2.28-12.66), and AUD (7.68; 2.59-22.81). Notably, 34% of adolescents with both depression and AUD subsequently experienced both these conditions as adults, compared to 7% of adolescents with only depression. Adolescents suffering only from depression were less likely than those with both conditions to experience suicidality (0.44; 0.21-0.95) and AUD in adulthood (0.18; 0.07-0.44). These findings underscore the clinical imperative to identify adolescents with this comorbidity. Recognition of the poor long-term prognosis can inform targeted interventions for this vulnerable group, ultimately improving health and well-being throughout the life course.

Objective: Depression is common, impairing, and the leading cause of disease burden in youths. This study aimed to identify the effects of childhood/adolescent depression on a broad range of longer-term outcomes.

Method: The analysis is based on the prospective, representative Great Smoky Mountains Study of 1,420 participants. Participants were assessed with the structured Child and Adolescent Psychiatric Assessment interview up to 8 times in childhood (age 9 similar to 16 years; 6,674 observations; 1993-2000) for DSM-based depressive disorders, associated psychiatric comorbidities, and childhood adversities. Participants were followed up 4 times in adulthood (ages 19, 21, 25, and 30 years; 4,556 observations of 1,336 participants; 1999-2015) with the structured Young Adult Psychiatric Assessment Interview for psychiatric outcomes and functional outcomes.

Results: In all, 7.7% of participants met criteria for a depressive disorder in childhood/adolescence. Any childhood/adolescent depression was associated with higher levels of adult anxiety and illicit drug disorders and also with worse health, criminal, and social functioning; these associations persisted when childhood psychiatric comorbidities and adversities were accounted for. No sex-specific patterns were identified. However, timing of depression mattered: individuals with adolescent-onset depression had worse outcomes than those with child-onset. Average depressive symptoms throughout childhood and adolescence were associated with more adverse outcomes. Finally, specialty mental health service use was protective against adult diagnostic outcomes.

Conclusion: Early depression and especially persistent childhood/adolescent depressive symptoms have robust, lasting associations with adult functioning. Some of these effects may be attenuated by service use.

Social anxiety disorder (SAD) can come in different forms, presenting problems for diagnostic classification. Here, we examined personality traits in a large sample of patients (N = 265) diagnosed with SAD in comparison to healthy controls (N = 164) by use of the Revised NEO Personality Inventory (NEO-PI-R) and Karolinska Scales of Personality (KSP). In addition, we identified subtypes of SAD based on cluster analysis of the NEO-PI-R Big Five personality dimensions. Significant group differences in personality traits between patients and controls were noted on all Big Five dimensions except agreeableness. Group differences were further noted on most lower-order facets of NEO-PI-R, and nearly all KSP variables. A logistic regression analysis showed, however, that only neuroticism and extraversion remained significant independent predictors of patient/control group when controlling for the effects of the other Big Five dimensions. Also, only neuroticism and extraversion yielded large effect sizes when SAD patients were compared to Swedish normative data for the NEO-PI-R. A two-step cluster analysis resulted in three separate clusters labelled Prototypical (33%), Introvert-Conscientious (29%), and Instable-Open (38%) SAD. Individuals in the Prototypical cluster deviated most on the Big Five dimensions and they were at the most severe end in profile analyses of social anxiety, self-rated fear during public speaking, trait anxiety, and anxiety-related KSP variables. While additional studies are needed to determine if personality subtypes in SAD differ in etiological and treatment-related factors, the present results demonstrate considerable personality heterogeneity in socially anxious individuals, further underscoring that SAD is a multidimensional disorder.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).

METHODS: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.

FINDINGS: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n=24) as compared to covert (n=22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p<0.0001) with more than three times higher response rate (50% vs. 14%; χ(2)(1)=6.91, p=0.009) and twice the effect size (d=2.24 vs. d=1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p≤0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p=0.0006) and attenuated amygdala (z threshold 2.70, p=0.003) activity.

INTERPRETATION: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.

FUNDING RESOURCES: The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).

Social anxiety disorder (SAD) is associated with altered brain function and structure, but most structural studies include small samples and findings are mixed. This study compared regional gray matter volume between 48 SAD patients and 29 healthy controls (HC) as well as the relationship between volume and symptom severity. Structural magnetic resonance images from SAD patients and HC were evaluated using standard voxel-based morphometry (VBM) processing in the SPM8 software package. Social anxiety symptom severity was rated in SAD patients by a clinician using the Liebowitz Social Anxiety Scale (LSAS). SAD patients had greater regional gray matter volume in the lingual gyrus and lateral occipital cortex than the controls, and within the SAD group a positive correlation was found between symptom severity and regional gray matter volume in the lingual gyrus and the retrosplenial cortex. These findings replicate and extend earlier reports of enlarged visual processing areas in SAD. Increased gray matter volume in regions involved in visual processing and self-consciousness could underlie, or be the result of, abnormal emotional information processing and self-focused attention previously demonstrated in patients with SAD.

Background: Correct prediction of treatment response is a central goal of precision psychiatry. Here, we tested the predictive accuracy of a variety of pre-treatment patient characteristics, including clinical, demographic, molecular genetic, and neuroimaging markers, for treatment response in patients with social anxiety disorder (SAD).

Methods: Forty-seven SAD patients (mean +/- SD age 33.9 +/- 9.4 years, 24 women) were randomized and commenced 9 weeks' Internet-delivered cognitive behavior therapy (CBT) combined either with the selective serotonin reuptake inhibitor (SSRI) escitalopram (20 mg daily [10 mg first week], SSRI+CBT, n= 24) or placebo (placebo+CBT, n= 23). Treatment responders were defined from the Clinical Global Impression-Improvement scale (CGI- I <= 2). Before treatment, patients underwent functional magnetic resonance imaging and the Multi-Source Interference Task taxing cognitive interference. Support vector machines (SVMs) were trained to separate responders from nonresponders based on pre-treatment neural reactivity in the dorsal anterior cingulate cortex (dACC), amygdala, and occipital cortex, as well as molecular genetic, demographic, and clinical data. SVM models were tested using leave-one-subject-out cross-validation.

Results: The best model separated treatment responders (n= 24) from nonresponders based on pre-treatment dACC reactivity (83% accuracy, P= 0.001). Responders had greater pre-treatment dACC reactivity than nonresponders especially in the SSRI+CBT group. No other variable was associated with clinical response or added predictive accuracy to the dACC SVM model.

Limitations: Small sample size, especially for genetic analyses. No replication or validation samples were available.

Conclusions: The findings demonstrate that treatment outcome predictions based on neural cingulate activity, at the individual level, outperform genetic, demographic, and clinical variables for medication-assisted Internet-delivered CBT, supporting the use of neuroimaging in precision psychiatry.

Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BP_ND) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [¹¹C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [¹¹C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BP_ND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment.

BACKGROUND: An individual's subjective perception of well-being is increasingly recognized as an essential complement to clinical symptomatology and functional impairment in children's mental health. Measurement of quality of life (QoL) has the potential to give due weight to the child's perspective.

SCOPE AND METHODOLOGY: Our aim was to critically review the current evidence on how childhood mental disorders affect QoL. First, the major challenges in this research field are outlined. Then we present a systematic review of QoL in children and adolescents aged 0-18 years formally diagnosed with a mental and behavioural disorder, as compared to healthy or typically developing children or children with other health conditions. Finally, we discuss limitations of the current evidence base and future directions based on the results of the systematic review and other relevant literature.

FINDINGS AND CONCLUSIONS: The systematic review identified 41 eligible studies. All were published after the year 2000 and 21 originated in Europe. The majority examined QoL in neurodevelopmental disorders, including attention-deficit hyperactivity disorder (k = 17), autism spectrum disorder (k = 6), motor disorders (k = 5) and intellectual disability (k = 4). Despite substantial heterogeneity, studies demonstrate that self-reported global QoL is significantly reduced compared to typical/healthy controls across several disorders and QoL dimensions. Parents' ratings were on average substantially lower, casting doubt on the validity of proxy-report. Studies for large diagnostic groups such as depressive disorders, anxiety disorders, (early onset) schizophrenia and eating disorders are largely lacking. We conclude that representative, well-characterized normative and clinical samples as well as longitudinal and qualitative designs are needed to further clarify the construct of QoL, to derive measures of high ecological validity, and to examine how QoL fluctuates over time and is attributable to specific conditions or contextual factors.

Background

Data suggest that certain psychological interventions can induce harm in a significant number of patients. While the need for adequate reporting of harms in clinical trials has repeatedly been emphasized, it is uncertain whether such information routinely is collected and reported in trials within this research field.

Method

We used the two major databases in clinical psychology and medicine (PsycINFO and PubMed) to identify original publications from 2010 reporting randomized controlled trials of psychological interventions for patients with mental and behavioral disorders. Two reviewers searched the full-text reports for information about monitoring of adverse events, side effects, and deterioration.

Results

Totally 132 eligible trials were identified. Only 28 trials (21%) included information that indicated any monitoring of harms on patient level. Four (3%) of these trials provided a description of adverse events as well as the methods used for collecting these data. Five of the trials (4%) reported adverse events but gave incomplete information about the method. An additional four reports (3%) briefly stated that no adverse events occurred, whereas 15 trials (11%) only provided information on deterioration or indicated monitoring of deterioration. The probability of including harm-related information was related to the journal impact factor.

Conclusion

Important information about harms is not reported systematically within this research field, suggesting that the risk of reporting bias is nontrivial in conclusions about the risk-benefit ratio of psychological treatments. Guidelines on how to define, detect, and report harms related to psychological interventions could facilitate better reporting.

Background

Attention-deficit/hyperactivity disorder (ADHD) in adolescence is associated with functional impairment in several domains of life. To enable development of interventions that more effectively target functional impairment in this age group, the associations between clinical characteristics and impairment need to be clarified. The aim of this study was to investigate the associations between ADHD and functional impairment, if they varied by sex, and the potential impact of comorbid psychiatric symptoms on the associations.

Methods

This was a cross-sectional study including adolescents with ADHD (n = 164) and a reference group of adolescents without ADHD (n = 106). Self-ratings and parental ratings of functional impairment in different life domains were used as outcomes in all analyses. Differences between groups were investigated with comparative analyses. General linear models (GLMs) were used to explore associations between ADHD symptoms and functional impairment in adolescents with ADHD, while adjusting for of comorbid symptoms, sex, and medication.

Results

Adolescents with ADHD displayed higher levels of functional impairment than peers without ADHD, and girls with ADHD rated higher impairment than their male counterparts. The combined ADHD presentation was associated with the highest levels of self-reported impairment, while parental ratings indicated comparable levels of overall impairment across presentations. In the adjusted GLMs, symptoms of inattention were strongly associated with self- and parent-rated impairment in school, but symptoms of hyperactivity/impulsivity were not, whereas symptoms of both inattention and hyperactivity/impulsivity were modestly associated with self-rated impairment with friends. Further, both emotional and conduct problems were associated with impairment in daily life.

Conclusions

Our results suggest that attention difficulties, in particular, seem to impair academic functioning in adolescents with ADHD, and interventions targeting such difficulties are warranted. In addition, comorbid symptoms need to be assessed and treated, and self-reports of functioning should be included in research and clinical practice involving adolescents.

AIMS: The few available studies on early-onset depression and future earnings offer ambiguous findings, and potential sources of heterogeneity are poorly understood. We examined the differences in adult earnings of males and females with and without a history of depressive disorder in adolescence, with specific focuses on (1) future earnings in clinical subtypes of adolescent depression; (2) the growth and distribution of earnings over time within these subgroups and (3) the mediating role of subsequent depressive episodes occurring in early adulthood.

METHODS: Data were drawn from the Uppsala Longitudinal Adolescent Depression Study, a community-based cohort study initiated in Uppsala, Sweden, in the early 1990s. Comprehensive diagnostic assessments were conducted at age 16-17 and in follow-up interviews 15 years later, while consecutive data on earnings for the years 1996 to 2016 (ages 20-40) were drawn from population-based registries. The current study included participants with a history of persistent depressive disorder (PDD) (n = 175), episodic major depressive disorder (MDD) (n = 82), subthreshold depression (n = 64) or no depression (n = 218) in adolescence. The association of adolescent depression with earnings in adulthood was analysed using generalised estimating equations. Estimates were adjusted for major child and adolescent psychiatric comorbidities and parental socioeconomic status. The indirect (mediated) effect of depression in early adulthood (ages 19-30) on earnings in mid-adulthood (31-40) was estimated in mediation analysis. The study followed the 'STrengthening the Reporting of OBservational studies in Epidemiology' (STROBE) guidelines.

RESULTS: Earnings across early to middle adulthood were lower for participants with a history of a PDD in adolescence than for their non-depressed peers, with an adjusted ratio of mean earnings of 0.85 (0.77-0.95) for females and 0.76 (0.60-0.95) for males. The differences were consistent over time, and more pronounced in the lower percentiles of the earnings distributions. The association was partially mediated by recurrent depression in early adulthood (48% in total; 61% for females, 29% for males). No reduction in earnings was observed among participants with episodic MDD in adolescence, while results for subthreshold depression were inconclusive.

CONCLUSIONS: Our findings suggest that future earnings of adolescents with depressive disorders are contingent on the duration and natural long-term course of early-onset depression, emphasising the need for timely and effective interventions to avoid loss of human capital.

Background Residential regions may impact the possibilities to achieve a sustainable working life (SWL, i.e. not having interruptions due to sickness absence, disability pension or unemployment) due to disparities in social security and labour market. We aimed to investigate concurrent trajectories of regions and SWL among Swedish twins. Methods National register data were used for the degree of SWL in each year, old-age pension, emigration, death and residential regions classified in three categories (cities; towns and suburbs; or rural areas) of Swedish twins in 1998-2016 (n = 80 398). Group-based multi-trajectory modelling and multinomial regression for relative risks with 95% confidence intervals were calculated. Results The six-group solution had the best fit to data with trajectories: stable living in towns and suburbs with SWL (33.8%); stable living in cities with SWL (22.1%); stable living in towns and suburbs with increasing SWL (13.9%); stable living in towns and suburbs with lack of SWL (13.2%); stable living towns and suburbs with decreasing SWL (8.8%); and stable living towns and suburbs with decreasing and ultimately lack of SWL (8.3%). Age and being woman increased and being married and higher education decreased the likelihood of belonging to groups 2-6 (vs. 1). Conclusions The simultaneous assessment of trajectories of three residential regions and SWL indicated that most people in Sweden seem to live continuously over time in towns and suburbs, but the degree of SWL may vary. More fine-grained assessment of residential regions would be needed to clarify the associations with SWL.

New insights into how depression is linked to physical health throughout the lifespan could potentially inform clinical decision making. The aim of this study was to explore the association of adolescent depression with subsequent prescriptions of anti-infectives and anti-inflammatories in adulthood. The study was based on the Uppsala Longitudinal Adolescent Depression Study (ULADS), a Swedish prospective cohort study initiated in 1991. Depressed (n = 321) and non-depressed (n = 218) adolescents were followed prospectively using patient registries. The associations of adolescent depression (age 16-17 years) with subsequent prescription of anti-infectives and anti-inflammatories (age 30-40 years), were analysed using generalized linear models. Sub -analyses explored the impact of diagnostic characteristics in adolescence and reception of anti-depressants prescriptions in adulthood. The results suggest that females with persistent depressive disorder in adolescence have a higher rate of future prescriptions than non-depressed peers, with adjusted incidence rate ratio of 1.42 (1.06 to 1.92) for anti-infectives and 1.72 (1.10 to 2.70) for anti-inflammatories. These associations were mainly driven by those who were also prescribed antidepressants during the same period. Associations were less robust for females with episodic or subsyndromal depression in adolescence and for males. These findings emphasize the importance of integrated mental health services at the primary healthcare level.

Background: Depression in adolescence is associated with increased healthcare consumption in adulthood, but prior research has not recognized the heterogeneity of depressive disorders. This paper investigated the additional healthcare usage and related costs in mid-adulthood for individuals with adolescent depression, and examined the mediating role of subsequent depression in early adulthood.

Methods: This study was based on the Uppsala Longitudinal Adolescent Depression Study, initiated in Sweden in the early 1990s. Depressive disorders were assessed in adolescence (age 16-17) and early adulthood (age 19-30). Healthcare usage and related costs in mid-adulthood (age 31-40) were estimated using nationwide population-based registries. Participants with specific subtypes of adolescent depression (n = 306) were compared with matched non-depressed peers (n = 213).

Results: Women with persistent depressive disorder (PDD) in adolescence utilized significantly more healthcare resources in mid-adulthood. The association was not limited to psychiatric care, and remained after adjustment for individual and parental characteristics. The total additional annual cost for a single age group of females with a history of PDD at a population level was estimated at 3.10 million USD. Depression recurrence in early adulthood mediated the added costs for psychiatric care, but not for somatic care.

Limitations: Primary health care data were not available, presumably resulting in an underestimation of the true healthcare consumption. Estimates for males had limited precision due to a relatively small male proportion.

Conclusions: On a population level, the additional healthcare costs incurred in mid-adulthood in females with a history of adolescent PDD are considerable. Early treatment and prevention should be prioritized.

Background: Adolescent depression has negative health and economic outcomes in the shortand long-term. Indicated preventive interventions, in particular group based cognitive behavioural therapy (GB-CBT), are ef-fective in preventing depression in adolescents with subsyndromal depression. However, little is known about the cost-effectiveness of these interventions. Methods: A Markov cohort model was used to conduct cost-effectiveness analyses comparing a GB-CBT indicated preventive intervention for depression, to a no-intervention option in a Swedish setting. Taking a time horizon of 5and 10 years, incremental differences in societal costs and health benefits expressed as differences in the proportion of cases of depression prevented, and as quality adjusted life years (QALYs) gained were estimated. Through univariate and probabilistic sensitivity analyses, the robustness of the results was explored. Costs, presented in 2018 USD, and effects were discounted at a yearly rate of 3%. Results: The base-case analysis showed that GB-CBT indicated preventive intervention incurred lower costs, prevented a larger proportion of cases of depression and generated higher QALYs compared to the no -intervention option for both time horizons. Offering the intervention was even a cost saving strategy and demonstrated a probability of being cost-effective of over 95%. In the sensitivity analyses, these results were robust to the modelling assumptions. Limitations: The study considered a homogeneous cohort and assumed a constant annual decay rate of the relative treatment effect. Conclusions: GB-CBT indicated preventive interventions for depression in adolescence can generate good value for money compared to leaving adolescents with subsyndromal depression untreated.

Objectives The aim of this study was to investigate associations between exposure to work-related violence/threats and harassment, and future sickness absence (SA) due to common mental disorders (CMDs), taking familial factors (shared genetics and early-life environment) and neuroticism into account.

Methods The study sample included 8795 twin individuals from the Swedish Twin Project of Disability Pension and Sickness Absence (STODS), including survey data from the Study of Twin Adults: Genes and Environment (STAGE). Self-reported work-related violence and/or threats as well as work-related harassment (including bullying) and national register data on SA due to CMDs were analyzed using standard logistic regression, and conditional logistic regression among complete twin pairs discordant on exposures. Individuals were followed for a maximum of 13 years. Interactions between neuroticism and exposures were assessed using both multiplicative and additive interaction analyses.

Results Exposure to work-related violence/threats was associated with higher odds of SA due to CMDs when adjusting for age, sex, marital status, children, education, type of living area, work characteristics, and symptoms of depression and burnout (OR 2.11, 95% CI 1.52-2.95). Higher odds of SA due to CMDs were also found for exposure to harassment (OR 1.52, 95% CI 1.10-2.11) and a combined indicator of exposure to violence/threats and/or harassment (OR 1.98, 95% CI 1.52-2.59), compared with the unexposed. Analyses of twins discordant on exposure, using the unexposed co-twin as reference, showed reduced ORs. These ORs were still elevated but no longer statistically significant, potentially due to a lack of statistical power. No multiplicative interaction was found between neuroticism and exposure to work-related violence/threats, or harassment. However, a statistically significant additive interaction was found between neuroticism and exposure to violence/threats, indicating higher odds of SA due to CMDs in the group scoring lower on neuroticism.

Conclusions Exposure to work-related offensive behaviors was associated with SA due to CMDs. However, the results indicated that these associations may be partly confounded by familial factors. In addition, an interaction between exposure and neuroticism was suggested. Thus, when possible, future studies investigating associations and causality between offensive behaviors at work and mental health-related outcomes, should consider familial factors and neuroticism.

Background: Social anxiety disorder (SAD) is associated with aberrant emotional information processing while little is known about non-emotional cognitive processing biases. The dorsal anterior cingulate cortex (dACC) has been implicated in SAD neuropathology and is activated both by emotional and non-affective cognitive challenges like the Multisource Interference Task (MSIT).

Methods: Here, we used fMRI to compare dACC activity and test performance during MSIT in 69 SAD patients and 38 healthy controls. In addition to patient-control comparisons, we examined whether neural activity in the dACC correlated with social anxiety, trait anxiety or depression levels.

Results: The MSIT activated the dACC as expected but with no differences in task performance or neural reactivity between SAD patients and controls. There were no significant correlations between dACC activity and social or trait anxiety symptom severity. In patients, there was a significant negative correlation between dACC activity and depressive symptoms.

Conclusions: In absence of affective challenge, we found no disorder-related cognitive profile in SAD patients since neither MSIT task performance nor dACC neural activity deviated in patients relative to controls.